Mycobacterium tuberculosis is the pathogen of tuberculosis. As a globally widespread and a fatal infectious disease, about more than 8 million people were infected annually and 2 million people died from tuberculosis, according to the World Health Organization. In the last decade, tuberculosis cases have increased at a rate of 20% worldwide, particularly in poor areas. If this trend continues, tuberculosis cases are very likely to continue to increase at a rate of 41% over the next two decades. In the first 50 years after the initial application of chemotherapy, tuberculosis had always been the main infectious disease leading to adult death, only second to AIDS. The complications of tuberculosis led to the emergence of many resistant strains, which also developed a symbiotic relationship with AIDS. The population infected with tuberculosis whose HIV tests were positive is 30 times more likely to develop into active tuberculosis compared to the population whose HIV tests were negative. On average, one out of every three people who died of AIDS was caused by tuberculosis.
The current treatments for tuberculosis use a combination of multiple agents. For example, a formula recommended by the U.S. Public Health Service includes a combination of isoniazid, rifampicin, pyrazinamide and ethambutol for two months, followed by a combination of isoniazid and rifampicin for four months. For patients infected with AIDS, use of this drug combination needs to be extended to seven months. For patients infected with multidrug-resistant tuberculosis, the drug combination needs contain additional drugs, such as ethambutol tablets, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofloxacin and ofloxacin.
For the benefit of patients and medical providers, new therapies that can improve the current treatment, such as a therapy that has a shorter treatment cycle or needs less supervision, are highly desired. During the first two months of treatment, the combined four drugs inhibited the bacteria, thereby greatly reducing the number of bacteria and making the patient non-infectious. In the next four to six months, the bacteria present in the patient's body were eliminated, thereby reducing the possibility of relapse. A potent antiseptic that shortens the treatment cycle to two months or less can bring huge benefits. At the same time, the drug should also require less supervision. Clearly, a drug that can shorten the treatment time while reduce the frequency of monitoring can bring the greatest benefit.
Complications of infectious tuberculosis cause multidrug-resistant tuberculosis. 4% of cases are associated with multidrug-resistant tuberculosis around the world. Multidrug-resistant tuberculosis is mainly resistant to isoniazid and rifampicin in the four standard therapy drugs. Multidrug-resistant tuberculosis can be fatal if leaving untreated or if the standard therapy for the common tuberculosis is used. Therefore, the treatment of such disease requires the use of second-line drugs to two years. Most of these second-line drugs are toxic, expensive, and of low efficacy. Due to the absence of effective treatment, patients with contagious drug-resistant tuberculosis continue to spread the disease. Therefore, for multidrug-resistant tuberculosis, a new drug having a new action mechanism is highly desired.
At present, in all clinical drugs, anti-tuberculosis ATP synthase inhibitors attract more and more attentions. WO2004/01436 described a compound which is effective for treating tuberculosis, in particular for tuberculosis infected with multidrug-resistant Mycobacterium tuberculosis. The compound has the formula (Ia):

According to that study, a novel anti-tuberculosis weapon, TMC207, was developed. The compound has the formula (Ic).

TMC207 (also known as R207910, or Compound ‘J’) is a diarylquinoline. The compound inhibits the proton pump of M. tuberculosis ATP synthase. TMC207 was obtained by Johnson & Johnson through screening more than 70,000 compounds against the saprophytic Mycobacterium smegmatis which grows more rapidly and controllably than M. tuberculosis does. TMC207 (Sirturo) is the first anti-tuberculosis and energy-metabolism-interfering drug that applied a new mechanism of action. The US Food and Drug Safety Agency and the European Commission approved Sirturo as part of a combination therapy for adult multidrug-resistant tuberculosis in late 2012 and March 2014, respectively.
The present invention aimed at developing a new type of pyridine derivatives which can inhibit the growth of mycobacterium, thereby achieving the effective treatment of the diseases caused by M. tuberculosis, M. bovis, M. avium, and M. marinum. 